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Synlett 2006(17): 2821-2823  
DOI: 10.1055/s-2006-950246
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a Heterobifunctional PEG Spacer Terminated with Aminooxy and Bromide Functionality

Christopher W. Dicus, Michael H. Nantz
Department of Chemistry, University of California Davis, Davis, CA 95616, USA
Fax: +1(502)8527214; e-Mail: michael.nantz@louisville.edu;
Further Information

Publication History

Received 12 June 2006
Publication Date:
09 October 2006 (online)

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Abstract

A simple and efficient synthesis of a novel heterobifunctional polyethylene glycol (PEG) spacer is described. The PEG spacer reagent is terminated with aminooxy and bromide functionality for ease of conjugation to a variety of electrophiles and/or nucleophiles.

Key words

heterobifunctional PEG - aminooxy - bioconjugation - molecular recognition - OEG - spacer

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1

Present address: Department of Chemistry, University of Louisville, Louisville, KY 40292, USA

19

For moisture-sensitive reactions, optimized yields were obtained only after drying the PEG intermediate by toluene azeotropic distillation immediately prior to use.

22

1H NMR and 13C NMR data (300 MHz and 75 MHz, respectively; in CDCl3) for all compounds: Compound 1a: 1H NMR: δ = 7.23 (br s, 1 H), 4.03 (m, 2 H), 3.82 (t, J = 6.3 Hz, 2 H), 3.74 (m, 2 H), 3.69 (app. s, 4 H), 3.48 (t, J = 6.3 Hz, 2 H), 1.48 (s, 9 H). 13C NMR: δ = 156.7, 81.7, 75.4, 71.2, 70.5, 70.4, 69.4, 30.2, 28.2.
Compound 1b: 1H NMR: δ = 7.59 (br s, 1 H), 4.03 (m, 2 H), 3.82 (t, J = 6.3 Hz, 2 H), 3.70-3.66 (m, 8 H), 3.48 (t, J = 6.3 Hz, 2 H), 1.48 (s, 9 H). 13C NMR: δ = 156.7, 81.5, 75.3, 71.2, 70.6 (3 C), 70.5, 69.3, 30.2, 28.2.
Compound 3a: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.44-7.35 (m, 6 H), 3.82 (t, J = 5.4 Hz, 2 H), 3.73-3.70 (m, 2 H), 3.66 (app. s, 4 H), 3.63 (m, 4 H), 2.17 (br s, 1 H), 1.05 (s. 9 H). 13C NMR: δ = 135.6, 133.6, 129.6, 127.6, 72.5, 70.8, 70.5, 63.4, 61.8, 26.8, 19.2.
Compound 3b: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.44-7.35 (m, 6 H), 3.82 (t, J = 5.4 Hz, 2 H), 3.73-3.70 (m, 2 H), 3.66-3.58 (m, 12 H), 2.25 (br s, 1 H), 1.05 (s, 9 H). 13C NMR: δ = 135.6, 133.6, 129.6, 127.6, 72.5, 72.4, 70.7, 70.7, 70.4, 63.4, 61.8, 26.8, 19.2.
Compound 4a: 1H NMR: δ = 7.83-7.80 (m, 2 H), 7.72-7.70 (m, 2 H), 7.70-7.65 (m, 4 H), 7.44-7.35 (m, 6 H), 4.36 (m, 2 H), 3.86 (m, 2 H), 3.74 (t, J = 5.4 Hz, 2 H), 3.65-3.62 (m, 2 H), 3.58-3.56 (m, 2 H), 3.52 (t, J = 5.4 Hz, 2 H), 1.03 (s, 9 H). 13C NMR: δ = 163.4, 135.6, 134.4, 133.7, 129.6, 129.0, 127.6, 123.4, 77.2, 72.4, 70.8, 70.7, 69.4, 63.3, 26.8, 19.2.
Compound 4b: 1H NMR: δ = 7.84-7.81 (m, 2 H), 7.74-7.71 (m, 2 H), 7.70-7.66 (m, 4 H), 7.44-7.34 (m, 6 H), 4.36 (m, 2 H), 3.85 (m, 2 H), 3.79 (t, J = 5.4 Hz, 2 H), 3.67-3.63 (m, 2 H), 3.61-3.52 (m, 8 H), 1.04 (s, 9 H). 13C NMR: δ = 163.4, 135.6, 134.4, 133.7, 129.6, 129.0, 127.6, 77.2, 72.4, 70.8, 70.7, 70.6, 70.5, 69.3, 63.4, 26.8, 19.2.
Compound 5a: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.44-7.35 (m, 6 H), 3.84 (m, 2 H), 3.81 (t, J = 5.4 Hz, 2 H), 3.69-3.59 (m, 8 H), 1.05 (s, 9 H). 13C NMR: δ = 135.6, 133.6, 129.6, 127.6, 74.7, 72.4, 70.7, 70.6, 69.7, 63.4, 26.8, 19.2.
Compound 5b: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.44-7.35 (m, 6 H), 3.85 (m, 2 H), 3.81 (t, J = 5.4 Hz, 2 H), 3.69-3.63 (m, 10 H), 3.60 (t, J = 5.4 Hz, 2 H), 1.05 (s, 9 H). 13C NMR: δ = 135.6, 133.6, 129.6, 127.6, 74.6, 72.4, 70.7, 70.6, 70.5, 70.5, 69.7, 63.4, 26.8, 19.2.
Compound 6a: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.51 (br s, 1 H), 7.44-7.34 (m, 6 H), 4.01 (m, 2 H), 3.82 (t, J = 5.4 Hz, 2 H), 3.72 (m, 2 H), 3.68-3.62 (m, 4 H), 3.61 (t, J = 5.4 Hz, 2 Hz), 1.46 (s, 9 H), 1.05 (s, 9 H). 13C NMR: δ = 156.7, 135.6, 133.6, 129.6, 127.6, 81.5, 75.3, 72.4, 70.7, 70.6, 69.4, 63.4, 28.2, 26.8, 19.2.
Compound 6b: 1H NMR: δ = 7.70-7.67 (m, 4 H), 7.62 (br s, 1 H), 7.44-7.34 (m, 6 H), 4.01 (m, 2 H), 3.81 (t, J = 5.4 Hz, 2 H), 3.70 (m, 2 H), 3.67-3.62 (m, 8 H), 3.60 (t, J = 5.4 Hz, 2 H), 1.46 (s, 9 H), 1.05 (s, 9 H). 13C NMR: δ = 156.7, 135.6, 133.6, 129.6, 127.6, 81.4, 75.3, 72.3, 70.7, 70.6, 70.5, 70.5, 69.2, 63.4, 28.2, 26.8, 19.1.
Compound 7a: 1H NMR: δ = 7.82 (br s, 1 H), 4.03 (m, 2 H), 3.76-3.72 (m, 4 H), 3.69 (s, 4 H), 3.64-3.61 (m, 4 H), 2.84 (br s, 1 H), 1.48 (s, 9 H). 13C NMR: δ = 156.8, 81.6, 75.2, 72.6, 70.4, 70.2, 69.2, 61.6, 28.2.
Compound 7b: 1H NMR: δ = 8.08 (br s, 1 H), 4.02 (m, 2 H), 3.74-3.66 (m, 12 H), 3.63 (m, 2 H), 2.80 (br s, 1 H), 1.48 (s, 9 H). 13C NMR: δ = 156.9, 81.4, 75.1, 72.6, 70.6, 70.4, 70.4, 70.3, 69.0, 61.7, 28.2.

24

Compound 9 was obtained as a single isomer: 1H NMR (600 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.58-7.57 (m, 2 H), 7.38-7.36 (m, 3 H), 4.34 (t, J = 4.6 Hz, 2 H), 3.83-3.81 (m, 4 H), 3.70 (app. s, 4 H), 3.46 (t, J = 6.0 Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 149.0, 132.2, 129.8, 128.7, 127.0, 73.5, 71.2, 70.7, 70.5, 69.7, 30.3.